Novel salt forms of isochroman-imidazole structured alpha-2a adrenoceptor agonist

Abstract

The present disclosure relates to novel salts, particularly crystalline salts of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) which are suitable for use in the manufacture of pharmaceutical compositions. Compound (I) is selective alpha2A adrenoceptor agonist and is useful in the treatment of anxiety, and for use as a sedative or analgesic agent, and other diseases were alpha2A agonism is desired.

1 . A salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) with an acid selected from the group consisting of naphthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, oxalic acid, saccharin, maleic acid, malonic acid, L-tartaric acid, fumaric acid, glycolic acid, glutaric acid, adipic acid, hydrobromic acid, mucic acid, 1-hydroxy-2-napthoic acid and hydrochloric acid. 
     
     
         2 . The salt according to  claim 1 , which is a salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) with an acid selected from the group consisting of naphthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, oxalic acid, saccharin, maleic acid, malonic acid, L-tartaric acid, glycolic acid, glutaric acid, adipic acid, hydrobromic acid, mucic acid and 1-hydroxy-2-napthoic acid. 
     
     
         3 . The salt according to  claim 1 , which is a salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) with an acid selected from the group consisting of napthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, oxalic acid and hydrobromic acid. 
     
     
         4 . The salt according to  claim 1 , which is crystalline. 
     
     
         5 . The salt according to  claim 1 , which is a crystalline napthalene-1,5-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         6 . The salt according to  claim 5 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 18.6±0.2, 19.1±0.2, 21.5±0.2, 22.4±0.2 and 23.9±0.2 degrees 2-theta. 
     
     
         7 . The salt according to  claim 1 , which is a crystalline ethane-1,2-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         8 . The salt according to  claim 7 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 13.5±0.2, 14.5±0.2, 16.0±0.2, 20.3±0.2 and 22.8±0.2 degrees 2-theta. 
     
     
         9 . The salt according to  claim 1 , which is a crystalline oxalic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         10 . The salt according to  claim 9 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 14.3±0.2, 17.0±0.2, 17.6±0.2, 19.8±0.2, 22.3±0.2 and 23.5±0.2 degrees 2-theta. 
     
     
         11 . The salt according to  claim 1 , which is a crystalline saccharin salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         12 . The salt according to  claim 11 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 14.1±0.2, 15.1±0.2, 15.8±0.2, 17.7±0.2 and 19.1±0.2 degrees 2-theta. 
     
     
         13 . The salt according to  claim 1 , which is a crystalline maleic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         14 . The salt according to  claim 13 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.2±0.2, 11.6±0.2, 16.8±0.2, 17.4±0.2 and 19.3±0.2 degrees 2-theta. 
     
     
         15 . The salt according to  claim 1 , which is a crystalline malonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         16 . The salt according to  claim 15 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.1±0.2, 10.8±0.2, 14.1±0.2, 16.3±0.2 and 17.4±0.2 degrees 2-theta. 
     
     
         17 . The salt according to  claim 1 , which is a crystalline L-tartaric acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         18 . The salt according to  claim 17 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 11.8±0.2, 12.5±0.2, 12.9±0.2, 13.4±0.2 and 14.0±0.2 degrees 2-theta. 
     
     
         19 . The salt according to  claim 1 , which is a crystalline fumaric acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         20 . The salt according to  claim 19 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 11.3±0.2, 13.2±0.2, 15.5±0.2, 22.5±0.2, 24.2±0.2 and 25.3±0.2 degrees 2-theta. 
     
     
         21 . The salt according to  claim 19 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.6±0.2, 15.9±0.2, 18.0±0.2, 22.1±0.2 and 26.4±0.2 degrees 2-theta. 
     
     
         22 . The salt according to  claim 1 , which is a crystalline glycolic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         23 . The salt according to  claim 22 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 11.5±0.2, 14.5±0.2, 17.4±0.2, 19.2±0.2, 20.6±0.2 and 25.3±0.2 degrees 2-theta. 
     
     
         24 . The salt according to  claim 1 , which is a crystalline glutaric acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         25 . The salt according to  claim 24 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 12.6±0.2, 16.0±0.2, 18.8±0.2, 19.9±0.2, and 21.2±0.2 degrees 2-theta. 
     
     
         26 . The salt according to  claim 1 , which is a crystalline adipic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         27 . The salt according to  claim 26 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.5±0.2, 12.1±0.2, 15.1±0.2, 18.3±0.2, 20.0±0.2 and 21.0±0.2 degrees 2-theta. 
     
     
         28 . The salt according to  claim 1 , which is a crystalline hydrobromic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         29 . The salt according to  claim 28 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 11.3±0.2, 16.9±0.2, 20.0±0.2, 22.7±0.2 and 24.3±0.2 degrees 2-theta. 
     
     
         30 . The salt according to  claim 1 , which is a crystalline mucic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         31 . The salt according to  claim 30 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 5.7±0.2, 11.9±0.2, 13.9±0.2, 17.0±0.2, 19.5±0.2 and 23.5±0.2 degrees 2-theta. 
     
     
         32 . The salt according to  claim 1 , which is a crystalline 1-hydroxy-2-napthoic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         33 . The salt according to  claim 32 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.6±0.2, 12.5±0.2, 15.3±0.2, 18.2±0.2 and 26.1±0.2 degrees 2-theta. 
     
     
         34 . The salt according to  claim 1 , which is a crystalline hydrochloric acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         35 . The salt according to  claim 34 , which is crystalline form characterized by an X-ray powder diffraction pattern comprising peaks at 10.7±0.2, 11.0±0.2, 12.6±0.2, 16.4±0.2 and 22.4±0.2 degrees 2-theta. 
     
     
         36 . A method of preparing the crystalline salt according to  claim 5 , comprising dissolving compound (I) and napthalene-1,5-disulfonic acid in acetone, adding water, cooling the mixture, and isolating the crystalline product. 
     
     
         37 . A method of preparing the crystalline salt according to  claim 7 , comprising dissolving compound (I) and ethane-1,2-disulfonic acid in 2-propanol, adding heptane, cooling the mixture, and isolating the crystalline product. 
     
     
         38 . A method of preparing the crystalline salt according to  claim 9 , comprising dissolving compound (I) and oxalic acid in acetone, cooling the mixture, and isolating the crystalline product. 
     
     
         39 . A method of preparing the crystalline salt according to  claim 28 , comprising dissolving compound (I) in 2-propanol follow by addition of hydrobromic acid, adding heptane, cooling the mixture, and isolating the crystalline product. 
     
     
         40 . A pharmaceutical composition comprising a salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) with an acid selected from the group consisting of naphthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, oxalic acid, saccharin, maleic acid, malonic acid, L-tartaric acid, fumaric acid, glycolic acid, glutaric acid, adipic acid, hydrobromic acid, mucic acid, 1-hydroxy-2-napthoic acid and hydrochloric acid as an active ingredient together with one or more excipients. 
     
     
         41 . A method of treating anxiety comprising administering a salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I) with an acid selected from the group consisting of naphthalene-1,5-disulfonic acid, ethane-1,2-disulfonic acid, oxalic acid, saccharin, maleic acid, malonic acid, L-tartaric acid, fumaric acid, glycolic acid, glutaric acid, adipic acid, hydrobromic acid, mucic acid, 1-hydroxy-2-napthoic acid and hydrochloric acid to a subject in need thereof. 
     
     
         42 . The pharmaceutical composition according to  claim 40 , wherein the salt is a crystalline napthalene-1,5-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         43 . The method of treating anxiety according to  claim 41 , wherein the salt is a crystalline napthalene-1,5-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         44 . The pharmaceutical composition according to  claim 40 , wherein the salt is a crystalline ethane-1,2-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         45 . The method of treating anxiety according to  claim 41 , wherein the salt is a crystalline ethane-1,2-disulfonic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         46 . The pharmaceutical composition according to  claim 40 , wherein the salt is a crystalline oxalic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         47 . The method of treating anxiety according to  claim 41 , wherein the salt is a crystalline oxalic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         48 . The pharmaceutical composition according to  claim 40 , wherein the salt is a crystalline hydrobromic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I). 
     
     
         49 . The method of treating anxiety according to  claim 41 , wherein the salt is a crystalline hydrobromic acid salt of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole (I).